US3074996A - Cyclohexylsulfamic acid salt - Google Patents

Description

3,074,996 CYtILOHEXYLSULFAMltZ ACiD SALT Henry M. N. Dickinson, Lake Bluli, Ili., assignor to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Filed Apr. 18, 1960, Ser. No. 22,686 1 Claim. (Cl. 260-465) The present invention relates to a new crystalline salt of u-(isopropyD-a (B-dimethylaminopropyl) -phenylacetonitrile. More particularly, the present invention relates to the cyclohexylsulfamic acid addition salt of the previously designated phenylacetonitrile base.

.In the formulation of certain pharmaceutical preparations, it is highly desirable to have the active ingredient in a solid physical form. This is due to the fact that most solid forms of compounds have greater stability than the liquid forms, are easier to handle, and in some instances, are more readily adaptable to certain formulations, such as tablets.

The previously described base, namely, m-(isopropyl)- u.([B-dimethylaminopropyl) -phenylacetonitrile, is sold under the trademark Peracon, and is Well known for its antitussive properties. In its normal physical form, a-(isopropyD-a (B-dimethylaminopropyl) phenylacetonitrile is a heavy, syrupy liquid and is bitter to the taste. It is apparent that bitterness is a very undesirable characteristic for an antitussive agent when orally administered.

It is well recognized in the pharmaceutical art that a therapeutic agent in a liquid state cannot easily be compounded in a tablet dosage form. A solid form is therefore preferred. Further, While some solid salt forms of compounds are stable, others are hygroscopic and unstable in the tablet formulations.

All attempts to find a solid form of the previously described base by forming the usual acid addition salts such as the hydrochloride, the sulfate and the phosphate have failed to produce a solid product. Attempts to form salts with saccharin and fumaric acids also failed to yield a solid form of the present base.

It is therefore .an object of the present invention to provide a therapeutically useful salt of a-(isopropyD-a- (,i-dimethylaminopropyl)-phenylacetonitrile which in its natural physical state is a solid product.

It is a further object of the present invention to provide a salt of the previously described base which has an improved taste.

"It is still a further object of the present invention to provide a salt of ot-(isopropyl)-a(,8-dimethylaminopropyl)phenylacetonitrile which is stable and nonhygroscopic.

Other objects of the present invention will be apparent to one skilled in the art from the accompanying description and claim to follow.

It has now been found that upon formation of the cyclohexylsulfamic acid addition salt of ot-(isopropyl)- m-(B-dimethylaminopropyl)-phenylacetonitrile, a therapeutically active compound is produced having the same antitussive proper-ties as the corresponding base. Cyclohexylsulfamic acid, unlike most acids, hase a sweet-sour taste. It is sold under the name of Hexamic Acid, a registered trademark of Abbott Laboratories. The novel salt of this invention has a mild, bittersweet taste which is much preferred over the strong, bitter taste of the base. In addition, the novel cyclohexylsulfamic acid addition salt is non-hygroscopic and therefore more stable.

The following specific examples are intended for the purpose of illustrating the present invention. They dfi l ifi ii Patented Jan. 22, 1953s ice should not be construed as limiting the invention to the precise reactants, ingredients, or conditions specified.

Example I ot-(Isopropyl)-rx-(B-dirnethylaminopropyl) phenylacetonitrile cyclohexylsulfamic acid l H3 N More NHson-r An aqueous mixture of cyclohexylsulfamic acid is prepared by slurrying 2.1154 gm. (0.0118 mole) of cyclohexylsulfamic acid in 5 ml. of Water. To the resulting aqueous mixture is added, at room temperature, 2.8845 gm. (0.0118 mole) of ot-(isopropyl)-ot (fi-dimethylaminopropyl)phenylacetonitrile. The reaction mixture is cooled and sufficient Water is thereafter added to give a total volume of 10.0 ml. Upon completion of the reaction, a solid precipitate forms which is recovered by filtration to obtain the desired product, ot-(iSOPIOPYD-oa- (/8din1ethylaminopropyl) -phenylacetonitrile cyclohexylsulfamic acid.

Analysis.--Calcd for C l-1 14 0 8: C, 62.3%; H, 8.8%; N, 9.92%; S, 0.075%. Found: C, 62.05%, H, 8.95%; N, 9.95%; S, 0.076%.

Example II This example illustrates the formulation of 2,000 tablets containing the novel salt of this invention as the active therapeutic agent. Tablets were made up to contain the following ingredients:

Amount ingredient: in grams m CisopropyD-u ([3 dimethylaminopropyl)- phenylacetonitrile cyclohexylsulfamic acid 50.0 Lactose 172.0 Acacia, powdered 5.6 Talc 5.6 Starch 12.0 Magnesium stearate 1.0 Water 20.0

Example 111 This example illustrates the formulation of the novel cyclohexylsulfamic acid salt of this invention in a liquid cough preparation. In this example, an expectorant, such as ipecac, and an antitussive agent, as represented by applicants novel salt, along with other ingredients are employed. The liquid preparation is formulated according to the following directions.

' of water with agitation.

Ingredient: Amount Benzoin compound solution, U.S.P ml 24.00 Sucrose gm 672.74 Sodium citrate, U.S.P gm 50.00 Ammonium chloride, U.S.P; gm 10.00 FDC, red dye #1 ..gm 0.10 Ipecac syrup, U.S.P ml 2.00 Glycerine gm 52.29

a-(isopropyD-a-(B dimethylaminopropyD- phenylacetonitrile cyclohexylsulfamic acid I gm 10.00 Menthol, -U.S.P., syntheticuus 'gm 0.04 Vanilla extract gm 0.20 Ethyl alcohol, U.S.P., 190 proof gm 5.40 Water, q.s rnl 1000 The benzoin solution is gradually added to 125 ml.

is. dissolved in 225 ml. of boiling water and allowed to cool to room temperature. The filtered benzoin solution is then added to the sucrose solution along with the sodium citrate and the ammonium chloride. The red The resulting solution is al-, lowed to stand for one hour and is filtered. The sucrose dye is dissolved in 8 ml. of water and the cyclohexylsulfamic acid salt is dissolved in 20 ml. of water and cornbined with the previously prepared solution to which is also added the ipecac and the glycerin'e. The menthol and the vanilla are dis'solvedinsuflicient alcohol and also added. To the final mixture is added sufiicient 4 water to give a total volume of one liter and the mixture thereafter filtered.

Through this invention a tablet 'form of a-(isopropyD- u-(fl-dimethylarninopropyl)-phenylacetonitrile cyclohexylsulfamic acid is provided which is stable and nonhygroscopic.

-As regards the use of the novel salt in a liquid preparation, a more'palatable product is now provided. No longer must a large amount of flavoring agents be added to mask the bitter taste of the a-(isopropyl)-ct-( 8-dimethylaminopropyl)-phenylaeetonitrile base, since the novel salt has a muchmilder, bittersweet taste.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to onesk-illed in the art. All such practice of the inventionv is considered to be a part thereof provided it falls within'the scope of the appended claim.

I claim:

The cyclohexylsulfamic acid addition salt of ot-(isopropyl).-o-(p-dirnethylaminopropyl)phenylacetonitrile.

References Cited in the file of this patent V UNITED STATES PATENTS Stuhmer et al Apr. 26, 1960 1956, page 330.